A number of ways are known for the synthesis of Rizatriptan (=3-[2-(dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)indole), and salts thereof, such as the benzoate. Rizatriptan is useful in the treatment of migraine. One known way (see EP 0 497 512 A2) for the synthesis is as follows: Alkylation of 1,2,4-triazol with 4-nitrobenzylchloride 1 leads to a mixture of two products resulting from alkylation of either the 1- or the 4-position of the triazole. The undesired 4-alkylation product can be removed (see Tetrahedron Lett. 1994, 35, 6981) or its formation can be avoided by alkylation of 4-amino-1,2,4-triazol and the subsequent removal of the 4-amino group by diazotation (see EP 0 573 221). Catalytic hydrogenation of the nitro group of 2 yields aniline 3 in quantitative amounts. Still it would be desirable to avoid the formation of the undesired 4-alkylation product, which is one of the problems to be solved by the present invention.
Diazotation of 3 and reduction of the diazonium salt with excess tin(II)chloride results in the phenyl hydrazone 6 (see J. Med. Chem. 1995, 38, 1799). However, tin salts are of low acceptability especially for pharmaceuticals, and in the form of sodium sulphite a more acceptable reducing agent was identified (see EP 0 573 221 A1).
The reaction of 6 or a salt of it under acidic conditions with aldehyde 5a or an acetal thereof produces, depending on the detailed reaction conditions, the tryptamine derivatives 4a or 4b, while with aldehyde 5b or an acetal thereof. Rizatriptan is directly obtained. Using 5b is preferable, as in this case Rizatriptan is obtained directly, though the synthesis via the dimethyl acetal of 5b requires additional steps (see J. Org. Chem. 1994, 59, 3738), whereas alkylation of dimethyl-amine with 4a or the reductive methylation of 4b give Rizatriptan only in relatively low yields.
The conversion of 3 into 6 and the subsequent Fischer-Indolisation with 5b may also be combined into a one-pot procedure (see EP 0 573 221 A1) to produce, after chromatography, Rizatriptan in 45% yield.

The low yields in the indole forming reaction have been attributed to “triazol polymerization”, the avoidance of which is another problem to be solved by the present invention, and led to other approaches (see WO 95/32197). There, a 2-iodo aniline such as 7, which is obtained via iodination of 3, is reacted with an alkyne 8 (with TES representing triethylsilyl) in the presence of a homogenous Pd-catalyst to give a mixture of the protected tryptopholes 9 and 10. These can be separated without a need for chromatography, and after deprotection of 9 the corresponding tryptophol can be transformed into Rizatriptan in 73% yield.

Although no additives such as triphenyl phosphine are required, a rather high loading of expensive homogenous palladium (e.g. 2 to 3 mol-%) is required to convert 7 into 9 and 10. Avoidance of the use of such a high palladium amount is another problem to be solved by the present invention.
Another approach to overcome the problems due to “triazole polymerisation” utilizes the Pd-catalysed coupling of a 2-halo or 2-trifluormethansulfonyl substituted aniline with an acyl silane. After de-silylation of the obtained 2-silyl indole derivatives, tryptanes such as Rizatriptan can be obtained (U.S. Pat. No. 5,808,064) (as well as Zolmitriptan, Almitriptan or Sumatriptan). Though this procedure is efficient, it suffers from the fact that acyl silanes are not readily available and still soluble (homogenous) palladium catalysts in high amount (e.g. 2 to 3 mol-%) are required. One of the problems to be solved by the present invention is to avoid the acyl silanes and the homogenous palladium catalysts.

The present invention presents a solution for the preparation of Rizatriptan, which avoids the disadvantages mentioned above associated with the Fischer indolisation procedure and also avoids the use of homogeneous palladium catalysts, thus especially solving the above-mentioned problems and offering further synthesis advantages.